Patricia J. Conrod

Understanding how the human brain matures from infancy through adolescence is essential for identifying factors that influence health outcomes. Magnetic resonance imaging (MRI) provides powerful tools for characterizing structural, microstructural, functional, and metabolic aspects of brain development; however, many pediatric imaging studies are constrained by small sample sizes, limited geographic diversity, lack of longitudinal measurement, restricted age ranges, and heterogeneous acquisition protocols. While recent large-scale neuroimaging consortia have begun to address these challenges, such resources remain limited in the Canadian context, creating a critical gap. The Canadian Pediatric Imaging Platform (C-PIP) has developed a multisite neuroimaging framework across three of Canada’s largest pediatric hospitals: Alberta Children’s Hospital (Calgary), Centre Hospitalier Universitaire Sainte-Justine (Montréal), and the Hospital for Sick Children (Toronto). These three sites were united through a national initiative, leveraging high-performance MRI systems to accelerate Canadian neurodevelopmental research. In addition, C-PIP has implemented a centralized data sharing infrastructure to facilitate open science and collaborative research across institutions. Here, we describe the development and implementation of a multimodal MRI acquisition protocol designed to support multimodal longitudinal studies of typical and atypical brain development spanning infancy through adolescence. Within-site stability and cross-site stability of C-PIP core MRI sequences were evaluated using a travelling-participant study. The C-PIP MRI protocol establishes a harmonized, multisite imaging framework that supports large-scale investigations of pediatric brain development and disorders. Highlights: The Canadian Pediatric Imaging Platform (C-PIP) is a national initiative acquiring longitudinal phenotyping and neuroimaging data from 820 children aged 0-18 years across three Canadian provinces (Alberta, Ontario and Québec). C-PIP has developed a harmonized, developmentally sensitive neuroimaging protocol to collect high-quality, comprehensive imaging data across multiple modalities. This paper outlines the development, considerations and implementation of the C-PIP neuroimaging protocol across sites. Preliminary cross-site validation analyses demonstrate good within- and between-site stability in neuroimaging measures. Graphical

Mounting evidence suggests that hierarchical psychopathology factors underlie psychiatric comorbidity. However, the exact neurobiological characterizations of these multilevel factors remain elusive. Here, leveraging the brain-behavior predictive framework with a 10-year longitudinal imaging-genetic cohort (IMAGEN, ages 14, 19 and 23, N = 1,750), we constructed 2 neural factors underlying externalizing and internalizing symptoms, which were reproducible across 6 clinical and population-based datasets (ABCD, STRATIFY/ESTRA, ABIDE II, ADHD-200 and XiNan, from age 10 to age 36, N = 3,765). These two neural factors exhibit distinct neural configurations: hyperconnectivity in impulsivity-related circuits for the externalizing symptoms and hypoconnectivity in goal-directed circuits for the internalizing symptoms. Both factors also differ in their cognitive-behavior relevance, genetic substrates and developmental profiles. Together with previous findings, we propose a hierarchical neurocognitive model of comorbid psychopathology (NeuroHiP) from preadolescence to adulthood, comprising a general neuropsychopathological factor (manifested as inefficient executive control) and two stratified factors of externalizing (deficient inhibition control) and internalizing (impaired goal-directed function) symptoms, respectively. These holistic insights are crucial for the development of stratified therapeutic interventions for mental disorders.

Importance: Substance use is a leading cause of burden of disease worldwide. Selective prevention programs can help reduce the development of problematic substance use and disorders. Objective: To examine effects of a selective, personality-targeted substance use prevention program on alcohol, cannabis, tobacco, nonmedical opioid, and illicit polysubstance use among adolescents with elevated levels of personality traits associated with frequent and risky substance use. Design, Setting, and Participants: This prespecified secondary analysis of a cluster-randomized clinical trial assessed the effectiveness of a personality-targeted cognitive-behavioral intervention (PreVenture) in reducing substance use during adolescence. Participants included grade 7 students attending 31 secondary schools in the Greater Montreal Area, Canada (2012-2013 school year), who screened as having elevated levels of anxiety sensitivity, hopelessness, impulsivity, or sensation seeking. Schools were randomized to either the intervention (15 schools) or the control group (16 schools). Data were analyzed in January to March 2025. Interventions: Schools delivered a 2-session, personality-targeted group-based cognitive-behavioral intervention designed to help students recognize, challenge, and manage personality-specific emotions, behaviors, and cognitions associated with substance use in adolescence. Main Outcomes and Measures: Self-reported frequency of alcohol, cannabis, smoking tobacco, nonmedical use of opioids, and illicit polysubstance use were measured by the Detection of Alcohol and Drug Problems in Adolescents. Results: A total of 3861 students from 31 schools were screened; 1669 students (847 [50.7%] female; mean [SD] age, 12.83 [0.47] years) were at elevated risk of substance use and included in the intention-to-treat sample. The 31 schools were randomized, with 16 schools with 964 students in the control group and 15 schools with 705 students in the intervention group. Multilevel bayesian mixed-effects models indicated that students in the intervention group had slower increases in the frequency of alcohol (odds ratio [OR], 0.92; 95% credible interval [CrI], 0.85-1.00), cannabis (OR, 0.75; 95% CrI, 0.66-0.86), tobacco smoking (OR, 0.79; 95% CrI, 0.70-0.96), and illicit polysubstance use (OR, 0.56; 95% CrI, 0.35-0.89) over 4 years. Effects did not differ by sex. Conclusions and Relevance: This secondary analysis of a cluster-randomized clinical trial found that personality-targeted interventions protected against the escalation in substance use during adolescence, with similar effects for males and females. Trial Registration: ClinicalTrials.gov Identifier: NCT01655615 .

There is an accumulation of evidence linking adolescent cannabis use with variations in brain structure and function, however it remains poorly understood whether cannabis-associated variations in brain structure represent pre-existing risk factors or consequences of cannabis use. We investigated whether cannabis use propensity and within-person variations of cannabis use were associated with cortical thickness during adolescence. Adolescents ( n = 136, 74 female) completed three neuroimaging sessions and annual assessments from 12 until 17 years of age (with 90% follow-up). Cannabis use was disaggregated into between- (vulnerability) and within-person (time-varying) components using longitudinal multi-level modelling, controlling for age, sex and alcohol use. Across the whole sample, cortical thickness was lower in years when participants’ cannabis use exceeded their own average level of cannabis use ( F _1,25663.3 = 3.96, p = 0.047; mean: −0.0023 mm/once-per-week increase). This effect was stronger in males ( F _1,11447.7 = 9.83, p = 0.0017), such that each once-per-week increase in cannabis use was associated with a 0.005 mm reduction in cortical thickness, comparable to 17.9% of the annual rate of cortical thinning (−0.028 mm/year). The strongest within-person effects of cannabis were observed in regions with the greatest expression of CNR1 , the gene that codes for the CB1 receptor (sample: rho = −0.33, p _spin = .025; males: rho = −0.5, p _spin = .005). At the between-person level, males (but not females) also exhibited a stable cortical thickness signature associated with propensity towards cannabis use and this signature was present before cannabis exposure. These results highlight the importance of longitudinal analyses using multi-level modelling to disaggregate potential risk factors from potential consequences of substance use.

Mounting evidence suggests hierarchical psychopathology factors underlying psychiatric comorbidity. However, the exact neurobiological characterizations of these multilevel factors remain elusive. In this study, leveraging the brain-behavior predictive framework with a 10-year longitudinal imaging-genetic cohort (IMAGEN, ages 14, 19 and 23, N = 1,750), we constructed two neural factors underlying externalizing and internalizing symptoms, which were reproducible across six clinical and population-based datasets (ABCD, STRATIFY/ ESTRA, ABIDE II, ADHD-200 and XiNan, from age 10 to age 36, N = 3,765). These two neural factors exhibit distinct neural configurations: hyperconnectivity in impulsivity-related circuits for the externalizing symptoms and hypoconnectivity in goal-directed circuits for the internalizing symptoms. Both factors also differ in their cognitive-behavior relevance, genetic substrates and developmental profiles. Together with previous studies, these findings propose a hierarchical neurocognitive spectral model of comorbid mental illnesses from preadolescence to adulthood: a general neuropsychopathological (NP) factor (manifested as inefficient executive control) and two stratified factors for externalizing (deficient inhibition control) and internalizing (impaired goal-directed function) symptoms, respectively. These holistic insights are crucial for the development of stratified therapeutic interventions for mental disorders.

Adolescence is a key period for neurocognitive maturation where deviation from normal developmental trajectories may be tied to adverse mental health outcomes. Cognitive disruptions have been noted in populations at risk for psychosis and are known to accompany periods of sleep deprivation. This study aims to assess the role of cognition as a mediator between sleep disruptions and psychosis risk. A cohort of 3801 high school students (51% female, mean age = 12.8, SD = 0.45 years) was recruited from 31 Montreal high schools. Measures of sleep, psychotic-like experiences, inhibition, working memory, perceptual reasoning, and delayed recall were collected from participants on a yearly basis over the five years of their high school education. A multi-level model mediation analysis was performed controlling for sex and time squared. Response inhibition was shown to be associated with, and to mediate (B = −0.005, SD = 0.003, p = 0.005*) the relationship between sleep disruptions (B = −0.011, SD = 0.004, p < 0.001*) and psychotic-like experiences (B = 0.411, SD = 0.170, p = 0.005*). Spatial working memory deficits on a given year were associated with a higher frequency of psychotic-like experiences that same year (B = −0.046, SD = 0.018, p = 0.005*) and the following year (B = −0.051, SD = 0.023, p = 0.010*), but were not associated with sleep disturbances. No significant associations were found between our variables of interest and either delayed recall or perceptual reasoning at the within person level. Findings from this large longitudinal study provide evidence that the association between sleep disruptions and psychosis risk is specifically mediated by inhibitory rather than general cognitive impairments. The association of spatial working memory, response inhibition, and sleep disruptions with psychotic-like experiences suggests that these factors may represent potential targets for preventative interventions.